Proteins such as PSD-95, hDlg, ZO-1, p55, Dsh, LIN-7, InaD, and PTPL1/FAP1 are known to possess the PDZ domain and are called the PDZ family. A structure having approximately 80 to 90 amino acid residues, repeated three times and each containing a conserved “Gly-Leu-Gly-Phe (GLGF)” 4 amino acid motif (Neuron 9:929–942 (1992)), was initially identified in the 95 KDa post-synaptic density protein, PSD-95. The same domain structure was later found in the Drosophila lethal (1) discs large-1 tumor suppressor protein, DlgA (Cell 66:451–464 (1991)), and in the tight junction protein, ZO-1 (J. Cell Biol. 121:491–502 (1993)). The repeat sequence was therefore named the “PDZ domain” by combining the initials of PSD-95, DlgA, and ZO-1. (It is also called the “GLGF repeat” or “DHR (DlgA homology region) domain.”) A protein having the PDZ domain is known to bind to other proteins by means of the sequence of this PDZ domain. For example, the PSD-95 protein is known to bind to the NMDA receptor 2B (Kornau, H. C., et al., Science 269:1737–1740 (1995)) and the Shaker-type K+ channel (Kim, E., et al., Nature 378:85–88 (1995)). The hDlg protein has been reported to bind directly to the protein encoded by the adenomatous polyposis coli tumor suppressor gene/APC (Matsumine et al., Science 272:1020–1023 (1996)), and the Dsh protein has been reported to bind directly to the Notch protein (Axelrod, J. D., et al., Science 271:1826–1832 (1996)). Furthermore, the InaD protein has been reported to bind to a Ca2+ channel protein, TRP, that functions in the Drosophila visual signal transduction cascade (Shieh, B. H. and Zhu, M. Y., Neuron 16:991–998 (1996)). The structure of proteins having the PDZ domain varies because some of the proteins contain only one domain (p55 and Dsh), while others contain two (SIP-1: Yanagisawa, J., et al., J. Biol. Chem. 272:7167–7172 (1997)), three (PSD-95 and hDlg), five (InaD and PTPL1/FAP1), seven (GRIP: Dong, H., et al., Nature 386:279–284 (1997)), or thirteen (Ullmer, C., et al., FEBS Letters 424:63–68 (1998)). Also a recently reported mouse gene lacks a region encoding an N-terminal peptide of the protein, but which encodes a peptide having four PDZ domains within this incomplete genetic region (Recorded to GenBank on May 18, 1997; accession number AF000168). Although there are a few exceptions, proteins having the PDZ domain are known to bind to other proteins that have a hydrophobic amino acid region consisting of three amino acids represented by “Thr/Ser-Xaa-Val” (Xaa being an arbitrary amino acid residue) at their C-terminus. Most of these proteins are transmembrane proteins and are presumed to function in signal transduction within the cell (TIBS 21:455–458 (1996), Yanagisawa, J., et al., J. Biol. Chem. 272:7167–7172 (1997)).
Since the above proteins having the PDZ domain and proteins that interact with these proteins are involved in neural transmission, apoptosis, and malignant conversion, they have recently drawn attention as targets for developing pharmaceuticals.